Neurotransmission Fault Due to Inherited Neurone Weakness

By Sharon KingmanStaff Writer

LONDON – Scientists have tracked the cause of a rare genetic condition that causes muscular weakness to a mutation affecting neurotransmission.

The mutation is in the gene that encodes a molecule that transports choline into the neuron at the neuromuscular junction. Choline is a vital raw material required for the synthesis of the neurotransmitter acetylcholine.

Although the condition studied, which is known as distal hereditary motor neuropathy Type VII (dHMN-VII), is very rare, the researchers who made the discovery said it is possible that other so-far-unexplained disorders of motor neurones may be caused by similar biological mechanisms.

Andrew Crosby, BDF Newlife professor of medical genetics at St George's University of London, said: "This genetic mechanism has never been linked with a disorder of motor neurones, so it indicates a new biological basis for this group of conditions. Knowledge of the biological pathway related to dHMN will potentially allow us to develop possible treatment options."

Crosby and his colleagues reported their study in the Dec. 7, 2012, issue of the American Journal of Human Genetics, in a paper, titled "Defective Presynaptic Choline Transport Underlies Hereditary Motor Neuropathy."

DHMN-VII is inherited in a dominant fashion. Those affected usually start to develop symptoms in their teens, although symptoms may appear as early as infancy or as late as the mid-thirties. Muscle weakness affects the hands and then the legs. The vocal cords may also become paralyzed, resulting in a hoarse voice.

The researchers previously studied a large UK family affected by dHMN-VII, and found that the gene responsible for inheritance of that disease was present in the chromosomal region 2q14. To pinpoint the exact gene, they sequenced the genome of a single affected individual from that family, looking for variants present in the 2q14 region. The only possible candidate was a single base deletion in a gene called SLC5A7, which encoded the presynaptic choline transporter (CHT). Further studies showed the variant was present in 14 affected members of the family, but not in 12 unaffected members. In addition, it was not present in 150 control individuals from the UK, or in genomic databases.

Investigation of the effect of the mutation showed that, during translation of the genetic message, the variant caused changes in the amino acid sequence together with a premature stop codon. As a result, the mutant CHT lost its final 82 amino acids – a part of the molecule that normally sits inside the cytoplasm of the cell. That section is highly conserved in many species, which suggested that its loss is likely to cause severe disruption of its function.

Beyond that, further experiments suggested that the mutant CHT has an adverse effect on the wild-type CHT. The researchers first found that the level of choline transport was lower in cells from individuals with dHMN-VII than in cells from control individuals. In addition, when they transfected cells from control individuals with copy DNA encoding both wild-type and dHMN-VII CHT, they found that the level of choline transport was significantly below what they would have expected.

That part of the study indicated the mutation has a "dominant-negative" effect: In other words, the mutant protein interferes with the function of the wild-type protein.

"This [study represents] a very promising step that may provide clues about other unexplained disorders of motor neurones caused by a similar biological disease mechanism," Crosby said. "A goal now is to investigate this biological mechanism in other patients with unexplained degenerative disorders of motor neurones."